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Etiology
Review: Statins are not associated with cognitive impairment, Alzheimer disease, or dementia
Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med. 2013;159:688-97.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ Question
Main results
Are statins associated with cognitive impairment or dementia?
Meta-analyses showed that statin exposure was not associated with increased risk for incident dementia, Alzheimer disease, or mild cognitive impairment (Table). 1 RCT (n = 5804) found no difference between statins and placebo for change in global cognitive performance (Mini-Mental State Examination) in patients who were cognitively intact at baseline (0.06, CI −0.04 to 0.16). Pooled-analysis of 3 RCTs (n = 1064) found that statin- and placebo-treated patients with cognitive impairment at baseline did not differ for change in cognitive performance (difference in score on Alzheimer disease Assessment Score–Cognitive Portion 0.11, 95% CI −1.76 to 1.97).
Review scope Included studies compared statin therapy with control in adults and evaluated cognitive function, including cognitive impairment, Alzheimer disease, and dementia.
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Library (all to Oct 2012) were searched for randomized controlled trials (RCTs), cohort studies, case–control studies, and cross-sectional studies published in English. Reference lists were searched. 57 studies met the selection criteria; 27 studies (3 RCTs, 16 cohort studies, 4 case–control studies, and 4 cross-sectional studies) were included in quantitative analyses.
Conclusion
Statins vs control for incident cognitive dysfunction*
Statins are not associated with increased risk for dementia, Alzheimer disease, or mild cognitive impairment in adults with no cognitive dysfunction; they do not affect cognitive performance in adults with or without cognitive impairment.
Outcomes
Source of funding: No external funding.
Dementia
Alzheimer disease
Mild cognitive impairment
Study type
Number of studies (n)
Risk ratio (95% CI)†
Cohort
10 {4 360 137}‡
0.87 (0.82 to 0.92)
Case–control
2 (2679)
0.25 (0.14 to 0.46)
Cross-sectional
1 (845)
0.54 (0.22 to 1.33)
Cohort
10 (759 553)
Case–control
3 {5758}‡
0.56 (0.41 to 0.78)
Cross-sectional
1 (57 104)
0.45 (0.35 to 0.58)
Cohort
4 {4019}‡
0.66 (0.51 to 0.86)
Case–control
1 (1040)
0.37 (0.16 to 0.84)
2 {24 595}‡
0.97 (0.87 to 1.09)
Cross-sectional
For correspondence: Dr. E.M. DeGoma, University of Pennsylvania Health System, Philadelphia, PA, USA. E-mail Emil.deGoma@ uphs.upenn.edu. ■
0.79 (0.63 to 0.99)
* CI defined in Glossary. †Fully adjusted risk ratios provided in each publication were used to calculate pooled estimates when available. ‡Data provided by author.
Commentary The meta-analyses by Richardson and colleagues and Swiger and colleagues provide important epidemiologic information to make sense of the US Food and Drug Administration (FDA) 2012 Consumer Update (1), which reported rare “memory loss, forgetfulness and confusion” and “ feeling ‘fuzzy’ or unfocussed” in patients receiving statins. Swiger and colleagues’ meta-analysis of 8 RCTs without excess bias showed no evidence of increased short-term dementia, and meta-analysis of 3 of the RCTs (n = 296) showed, with the Digit Symbol Substitution Test, a nonsignificant trend of an improved cognition score. More important, sensitivity analysis of 5 longterm trials assessing new dementia found an absolute risk reduction of 2% (95% CI 1 to 3) at 6 years, with a number needed to prevent dementia of 50 (CI 33 to 100). 2 large, important cardiovascular prevention RCTs were excluded from the Swiger meta-analysis because dementia was not assessed JC10
© 2014 American College of Physicians
at both baseline and follow-up. The Heart Protection Study (2) randomized 20 536 UK adults 40 to 80 years of age to simvastatin, 40 mg, or placebo for 5 years and found a 25% reduction in nonfatal myocardial infarction and an 18% reduction in coronary death. Using the Telephone Interview for Cognitive Status questionnaire to assess cognitive impairment at the final visit, the authors found that functional scores did not differ between simvastatin and placebo groups (2). PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) used more sophisticated testing (4 tests of global cognitive function 6 times over 42 mo) in patients 70 to 82 years of age and found no difference between pravastatin and control groups (3). Richardson and colleagues assessed the effect of statins on 3 outcomes: dementia, Alzheimer disease, and mild cognitive impairment. In the absence of an RCT, pooled meta-analysis of 3 cohort studies at lowest risk for bias suggested a reduced incidence (continued on page 11) 20 May 2014 | ACP Journal Club | Volume 160 • Number 10
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Etiology
Review: Statins are not associated with cognitive impairment or dementia in cognitively intact adults
Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013;88:1213-21.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ N ★★★★★✩✩ Question In adults with no cognitive dysfunction, are statins associated with short-term cognitive impairment or long-term dementia?
Statins vs placebo in adults with no cognitive dysfunction* Outcomes
Number of trials (n)
Mean difference (95% CI)
Short-term cognition†
3 (296)
1.65 (−0.03 to 3.32)
Long-term dementia‡
8 (23 443)
0.71 (0.61 to 0.82)
Hazard ratio (CI)
Review scope Included studies compared any statin with control in adults with no history of cognitive dysfunction. The short-term (< 1 y after drug initiation) outcome was cognitive impairment, and the long-term (≥ 1 y after drug initiation) outcome was dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision).
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Central Register (all to Apr 2013) were searched for randomized controlled trials (RCTs) and, for long-term outcomes, high-quality prospective cohort studies. Reference lists were searched, and experts were consulted. 8 short-term RCTs and 8 long-term studies (mean exposure duration 3 to 25 y) met the selection criteria. Of the long-term studies, the outcome was specifically Alzheimer disease in 3 studies and dementia in 5 studies.
*CI defined in Glossary. †< 1 y of treatment initiation. Positive difference favors statins. ‡≥ 1 y after treatment initiation (mean 3 to 25 y).
Main results Meta-analysis showed that statin exposure was not associated with greater risk for impaired short-term cognition or long-term dementia (Table).
Conclusion In adults with no cognitive dysfunction, statins do not increase risk for short-term cognitive impairment or long-term dementia. Source of funding: No external funding. For correspondence: Dr. S.S. Martin, Johns Hopkins Hospital, Baltimore, MD, USA. E-mail [email protected]. ■
Commentary (continued from page 10) of Alzheimer disease with statins compared with no statins (relative risk, 0.57, CI 0.42 to 0.77). But 3 RCTs in patients with Alzheimer disease showed no cognitive improvement. The RCT with lowest risk for bias (n = 20 536) (2) showed no difference in dementia prevention between statins and placebo. Through examination of FDA databases, Richardson and colleagues found that reported rates of cognitive-related adverse events were no higher for statins than for 2 drugs not known to cause cognitive impairment—losartan and clopidogrel (1.9 vs 1.6 and 1.9 per million written prescriptions). This and the results of both meta-analyses are reassuring to physicians who prescribe statins but may be less so to patients who experience cognitive changes. The only response may be to stop statin use for an indefinite period to determine whether improvement occurs, which has been shown in many case reports. For cardioprotective purposes, one can try other low-density lipoprotein-cholesterol-lowering, 20 May 2014 | ACP Journal Club | Volume 160 • Number 10
RCT-proven, cardioprotective drugs, such as bile acid binders or niacin. If amenable to patients at higher cardiovascular risk, alternate-day dosing of longer-acting low-dose statins might be tried after pretreatment function returns. Donald A. Smith, MD, MPH Icahn School of Medicine at Mount Sinai New York, New York, USA References 1. US Food and Drug Administration. Consumer Health Information. FDA expands advice on statin risks. 2012. www.fda.gov/ForConsumers/ ConsumerUpdates/ucm293330.htm (accessed 6 March 2014). 2. Heart Protection Study Collaborative Group. MRC/BHY Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360:7-22. 3. Trompet S, van Vliet P, de Craen AJ, et al. Pravastatin and cognitive function in the elderly. Results of the PROSPER study. J Neurol. 2010;257:85-90.
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a University of California San Diego User on 01/16/2017
JC11
Etiology
Review: Statins are not associated with cognitive impairment, Alzheimer disease, or dementia
Richardson K, Schoen M, French B, et al. Statins and cognitive function: a systematic review. Ann Intern Med. 2013;159:688-97.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★✩✩ Question
Main results
Are statins associated with cognitive impairment or dementia?
Meta-analyses showed that statin exposure was not associated with increased risk for incident dementia, Alzheimer disease, or mild cognitive impairment (Table). 1 RCT (n = 5804) found no difference between statins and placebo for change in global cognitive performance (Mini-Mental State Examination) in patients who were cognitively intact at baseline (0.06, CI −0.04 to 0.16). Pooled-analysis of 3 RCTs (n = 1064) found that statin- and placebo-treated patients with cognitive impairment at baseline did not differ for change in cognitive performance (difference in score on Alzheimer disease Assessment Score–Cognitive Portion 0.11, 95% CI −1.76 to 1.97).
Review scope Included studies compared statin therapy with control in adults and evaluated cognitive function, including cognitive impairment, Alzheimer disease, and dementia.
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Library (all to Oct 2012) were searched for randomized controlled trials (RCTs), cohort studies, case–control studies, and cross-sectional studies published in English. Reference lists were searched. 57 studies met the selection criteria; 27 studies (3 RCTs, 16 cohort studies, 4 case–control studies, and 4 cross-sectional studies) were included in quantitative analyses.
Conclusion
Statins vs control for incident cognitive dysfunction*
Statins are not associated with increased risk for dementia, Alzheimer disease, or mild cognitive impairment in adults with no cognitive dysfunction; they do not affect cognitive performance in adults with or without cognitive impairment.
Outcomes
Source of funding: No external funding.
Dementia
Alzheimer disease
Mild cognitive impairment
Study type
Number of studies (n)
Risk ratio (95% CI)†
Cohort
10 {4 360 137}‡
0.87 (0.82 to 0.92)
Case–control
2 (2679)
0.25 (0.14 to 0.46)
Cross-sectional
1 (845)
0.54 (0.22 to 1.33)
Cohort
10 (759 553)
Case–control
3 {5758}‡
0.56 (0.41 to 0.78)
Cross-sectional
1 (57 104)
0.45 (0.35 to 0.58)
Cohort
4 {4019}‡
0.66 (0.51 to 0.86)
Case–control
1 (1040)
0.37 (0.16 to 0.84)
2 {24 595}‡
0.97 (0.87 to 1.09)
Cross-sectional
For correspondence: Dr. E.M. DeGoma, University of Pennsylvania Health System, Philadelphia, PA, USA. E-mail Emil.deGoma@ uphs.upenn.edu. ■
0.79 (0.63 to 0.99)
* CI defined in Glossary. †Fully adjusted risk ratios provided in each publication were used to calculate pooled estimates when available. ‡Data provided by author.
Commentary The meta-analyses by Richardson and colleagues and Swiger and colleagues provide important epidemiologic information to make sense of the US Food and Drug Administration (FDA) 2012 Consumer Update (1), which reported rare “memory loss, forgetfulness and confusion” and “ feeling ‘fuzzy’ or unfocussed” in patients receiving statins. Swiger and colleagues’ meta-analysis of 8 RCTs without excess bias showed no evidence of increased short-term dementia, and meta-analysis of 3 of the RCTs (n = 296) showed, with the Digit Symbol Substitution Test, a nonsignificant trend of an improved cognition score. More important, sensitivity analysis of 5 longterm trials assessing new dementia found an absolute risk reduction of 2% (95% CI 1 to 3) at 6 years, with a number needed to prevent dementia of 50 (CI 33 to 100). 2 large, important cardiovascular prevention RCTs were excluded from the Swiger meta-analysis because dementia was not assessed JC10
© 2014 American College of Physicians
at both baseline and follow-up. The Heart Protection Study (2) randomized 20 536 UK adults 40 to 80 years of age to simvastatin, 40 mg, or placebo for 5 years and found a 25% reduction in nonfatal myocardial infarction and an 18% reduction in coronary death. Using the Telephone Interview for Cognitive Status questionnaire to assess cognitive impairment at the final visit, the authors found that functional scores did not differ between simvastatin and placebo groups (2). PROSPER (Prospective Study of Pravastatin in the Elderly at Risk) used more sophisticated testing (4 tests of global cognitive function 6 times over 42 mo) in patients 70 to 82 years of age and found no difference between pravastatin and control groups (3). Richardson and colleagues assessed the effect of statins on 3 outcomes: dementia, Alzheimer disease, and mild cognitive impairment. In the absence of an RCT, pooled meta-analysis of 3 cohort studies at lowest risk for bias suggested a reduced incidence (continued on page 11) 20 May 2014 | ACP Journal Club | Volume 160 • Number 10
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a University of California San Diego User on 01/16/2017
Etiology
Review: Statins are not associated with cognitive impairment or dementia in cognitively intact adults
Swiger KJ, Manalac RJ, Blumenthal RS, Blaha MJ, Martin SS. Statins and cognition: a systematic review and meta-analysis of short- and long-term cognitive effects. Mayo Clin Proc. 2013;88:1213-21.
Clinical impact ratings: F ★★★★★★✩ C ★★★★★★✩ N ★★★★★✩✩ Question In adults with no cognitive dysfunction, are statins associated with short-term cognitive impairment or long-term dementia?
Statins vs placebo in adults with no cognitive dysfunction* Outcomes
Number of trials (n)
Mean difference (95% CI)
Short-term cognition†
3 (296)
1.65 (−0.03 to 3.32)
Long-term dementia‡
8 (23 443)
0.71 (0.61 to 0.82)
Hazard ratio (CI)
Review scope Included studies compared any statin with control in adults with no history of cognitive dysfunction. The short-term (< 1 y after drug initiation) outcome was cognitive impairment, and the long-term (≥ 1 y after drug initiation) outcome was dementia (Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision).
Review methods MEDLINE, EMBASE/Excerpta Medica, and Cochrane Central Register (all to Apr 2013) were searched for randomized controlled trials (RCTs) and, for long-term outcomes, high-quality prospective cohort studies. Reference lists were searched, and experts were consulted. 8 short-term RCTs and 8 long-term studies (mean exposure duration 3 to 25 y) met the selection criteria. Of the long-term studies, the outcome was specifically Alzheimer disease in 3 studies and dementia in 5 studies.
*CI defined in Glossary. †< 1 y of treatment initiation. Positive difference favors statins. ‡≥ 1 y after treatment initiation (mean 3 to 25 y).
Main results Meta-analysis showed that statin exposure was not associated with greater risk for impaired short-term cognition or long-term dementia (Table).
Conclusion In adults with no cognitive dysfunction, statins do not increase risk for short-term cognitive impairment or long-term dementia. Source of funding: No external funding. For correspondence: Dr. S.S. Martin, Johns Hopkins Hospital, Baltimore, MD, USA. E-mail [email protected]. ■
Commentary (continued from page 10) of Alzheimer disease with statins compared with no statins (relative risk, 0.57, CI 0.42 to 0.77). But 3 RCTs in patients with Alzheimer disease showed no cognitive improvement. The RCT with lowest risk for bias (n = 20 536) (2) showed no difference in dementia prevention between statins and placebo. Through examination of FDA databases, Richardson and colleagues found that reported rates of cognitive-related adverse events were no higher for statins than for 2 drugs not known to cause cognitive impairment—losartan and clopidogrel (1.9 vs 1.6 and 1.9 per million written prescriptions). This and the results of both meta-analyses are reassuring to physicians who prescribe statins but may be less so to patients who experience cognitive changes. The only response may be to stop statin use for an indefinite period to determine whether improvement occurs, which has been shown in many case reports. For cardioprotective purposes, one can try other low-density lipoprotein-cholesterol-lowering, 20 May 2014 | ACP Journal Club | Volume 160 • Number 10
RCT-proven, cardioprotective drugs, such as bile acid binders or niacin. If amenable to patients at higher cardiovascular risk, alternate-day dosing of longer-acting low-dose statins might be tried after pretreatment function returns. Donald A. Smith, MD, MPH Icahn School of Medicine at Mount Sinai New York, New York, USA References 1. US Food and Drug Administration. Consumer Health Information. FDA expands advice on statin risks. 2012. www.fda.gov/ForConsumers/ ConsumerUpdates/ucm293330.htm (accessed 6 March 2014). 2. Heart Protection Study Collaborative Group. MRC/BHY Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomized placebo-controlled trial. Lancet 2002;360:7-22. 3. Trompet S, van Vliet P, de Craen AJ, et al. Pravastatin and cognitive function in the elderly. Results of the PROSPER study. J Neurol. 2010;257:85-90.
© 2014 American College of Physicians
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930210/ by a University of California San Diego User on 01/16/2017
JC11
